We describe a high radiochemical yield late-stage direct 18F-labeling of bare biomolecules containing common active groups. Spontaneity and site-selectivity are attributed to the remarkably higher rates of nucleophilic substitution reactions on phosphonates than on other electrophiles by F– at various hydrogen bond forms. Rapid access to many medicinally significant 18F-labeled biomolecules is achieved at 21–68% radiochemical yields and 35.9–55.1 GBq μmol–1 molar activities both manually or automatically.

18 F-Labeling methods for the preparation of 18 F-labeled molecular probes can be classified into electrophilic fluorination, nucleophilic fluorination, metal-F coordination, and 18 F/ 19 F isotope exchange. Isotope exchange-based 18 F-labeling methods demonstrate mild conditions featuring water resistance and facile high-performance liquid chromatography-free purification in direct 18 F-labeling of substrates. This paper systematically reviews isotope exchange-based 18 F-labeling methods sorted by the adjacent atom bonding with F, i.e., carbon and noncarbon atoms (Si, B, P, S, Ga, Fe, etc.). The respective isotope exchange mechanism, radiolabeling condition, radiochemical yield, molar activity, and stability of the 18 F-product are mainly discussed for each isotope exchange-based 18 F-labeling method as well as the cuttingedge application of the corresponding 18 F-labeled molecular probes.

Radiochemical yields (RCYs) of isotope exchange-based 18 F-fluorination of non-carbon-centered substrates in water are rationally enhanced by adding surfactants, which increases both the rate constant k and local reactant concentrations. Among 12 surfactants, the cationic surfactant cetrimonium bromide (CTAB) and two nonionic surfactants (Tween 20 and Tween 80) were selected for their superior catalytic effects, namely, electrostatic effects or solubilization effects. For a model substrate, bis(4methoxyphenyl)phosphinic fluoride, the 18 F-fluorination rate constant (k) increased up to 7-fold, while its saturation concentration rose up to 15-fold due to micelle formation, encapsulating 70−94% of the substrate. With 30.0 mmol/L CTAB, the required 18 F-labeling temperature of a typical organofluorosilicon prosthesis ([ 18 F]SiFA) decreased from 95 °C to room temperature, achieving an RCY of 22%. For an E[c(RGDyK)] 2 -derived peptide tracer with an organofluorophosphine prosthesis, the RCY in water at 90 °C achieved 25%, correspondingly increasing the molar activity (A m ). After high-performance liquid chromatography (HPLC) or solid-phase purification, the residual selected surfactant concentrations in the tracer injections were well below the FDA DII (Inactive Ingredient Database) limits or the LD50 in mice.

No abstract